We recorded and followed up the complete pathogenesis of 18 patients with non-severe COVID-19 infection in a hospital in Beijing, and recorded the dynamic changes of a total of 235 virus results. Although they develop the disease together, their clinical processes are quite different. It is particularly noteworthy that in these non-severe patients, the negative conversion of the virus with mild lung lesions is very slow. This plays an important role in preventing and controlling the spread of COVID-19, that is, patients with mild symptoms may be quarantined for longer. The possible mechanisms are shown in Fig. 5
When the virus invades the human body, it mainly binds to the ACE2 receptor on type II alveolar epithelial cells, thus causing damage to the structural integrity of the alveoli. At the same time, the body's innate immune system is activated. At present, the known PRRs mainly includes Toll-like receptor (TLR), Rig-I-like receptor (RLR), Nod-like receptor (NLR), C-type lectin-like receptor and other ways[14–18]. We will focus on TLR, RLR, and RLR.
The activation of TLR occurs mainly in antigen presenting cells, such as dendritic cells (DC), macrophages, monocytes and B cells. After recognizing the viral components, TLR recruits signal transduction molecules containing Toll/IL-1 receptor (TIR), such as myeloid differentiation primary response protein 88 (MyD88) and interferon-β TIR domain junction protein (TRIF), and then MyD88 and TRIF stimulate MAPK and NF- κB pathways, thereby enhancing the production of IFN and pro-inflammatory factors[16, 19].
RLR is a family of cytoplasmic receptors, composed of three members, RIG-I, MDA5 (melanoma differentiation associated factor 5), and LGP2 (laboratory of genetics and physiology 2)[20–22]. RIG-I recognizes the 5'- triphosphate part of the viral genomic RNA and the double-stranded structure formed by self-annealing at the complementary ends of the viral genome. On the contrary, MDA5 usually detects longer dsRNA sequences. The combination of RIG-1 and MDA5 with viral RNA results in conformational changes, which exposes the CARD domain. Next, MAVS, an antiviral signal transducer located in mitochondria and peroxisome, was recruited to trigger the expression of IFN and proinflammatory cytokines.
NLR is another large family of PRR[23, 24]. LRR motif detects viral PAMP, to induce structural rearrangement. Subsequently, a variety of signal pathways, including MAPK and NF- κB signal pathways, are activated. At the same time, the assembly of inflammatory bodies is also mediated by members of the NLR family. Inflammatory bodies activate inflammatory-related proteases and induce the cleavage of IL-1 β and IL-18 precursors into active forms. The infection of coronavirus is related to the inhibition of IFN synthesis. The ability of virus to regulate type I IFN signal transduction is an important indicator of virus virulence.
In the early stage of virus infection, it is mainly innate immunity. This includes the barrier effect of virus invasion site, phagocytosis of phagocytes, antimicrobial substances in body fluids (such as complement and lysozyme), interferon and NK cells[26–28]. Among them, IFN and NK cells play a more important role. It plays a major immune role in preventing virus invasion, killing and eliminating virus, and terminating infection. Adaptive immunity appears late, including cellular immunity and humoral immunity. Viruses are strictly intracellular parasitic acellular microorganisms. This determines that cellular immunity plays a leading role in the process of eliminating virus infection, but antibodies can neutralize the virus outside the cell, making the virus lose its adhesion and infectivity to host cells. It also plays an important role in the process of anti-infection and spread[27, 29].
Interferon cannot directly inactivate the virus, but through binding to the interferon receptor on the surface of the host cell to induce the synthesis of a variety of antiviral proteins, so as to achieve the inhibition of the virus. The main functions of antiviral proteins include degrading viral mRNA, blocking viral transcription and translation, inhibiting viral protein synthesis, terminating viral replication and so on. Virus-infected cells produce and release interferon at the same time as the virus replicates, and quickly induces neighboring cells to produce interferon[27, 28]. Therefore, interferon can not only limit the proliferation of the virus in infected cells, but also limit the spread of the virus between cells. IFN-α and IFN- β can not only activate macrophages and NK cells, but also promote the expression of MHC class I antigens in virus infected cells, which is beneficial for CTL to play a lethal role. IFN- γ not only has antiviral effect, but also induces antigen presenting cells to express MHC II antigens, enhances the recognition process of specific immunity, enhances the killing function of NK cells, macrophages and CTL, and promotes the transformation of Th0 cells into Th1 cells[25, 30].
NK cells can kill virus-infected cells directly and non-specifically without antigen pre-sensitization. The killing effect of NK cells appears quickly, so it plays an important role in the process of immune surveillance and early anti-infective immunity. In addition, after NK cells are activated, they can also release cytokines such as IFN- γ and TNF, and regulate the immune function of the body.[31, 32]
Adaptive immunity plays an important role in anti-viral infection. CTL is a key adaptive immune effector cell, and its killing effect is limited by MHC class I molecules[33, 34]. It kills virus-infected cells by releasing perforin and granzyme or inducing apoptosis of target cells. After killing one target cell, CTL can continue to kill other target cells without damage itself, which reflects the high efficiency of anti-virus in the body. The maturation and activation of CTL need the assistance of CD4 + T cells. IL-2 and IFN- γ can activate and enhance the killing function of CTL. When the infected cells were dissolved by CTL and released virus particles, the neutralization of antibody and the phagocytosis of phagocytes were initiated immediately, and the blocking effect of neutralization antibody and the further amplification of phagocytosis and killing effect of conditioning antibody on effector cells were further amplified, and the virus particles could be eliminated finally[35, 36]. Th cells can exert antiviral effect by secreting cytokines. In addition, humoral immunity also plays an important role in anti-virus and preventing the spread of virus infection[33–36].
As explained above, innate immunity and adaptive immunity play an important role in fighting viral infection, eliminating the SARS-CoV-2 in different ways. This also directly or indirectly explains that in non-severe COVID-19 patients, patients with mild or no lung injury, because the immune system has not been fully activated, the inflammatory response is mild, the immune system antivirus is slower, and the virus is carried for a long time.
This study also has some inevitable limitations. First of all, the number of cases included is relatively small, but we have made up for some defects in some aspects through detailed course records and follow-up. Secondly, as COVID-19 is an emerging infectious disease, and medical supplies are relatively scarce, we are unable to quantitatively detect the virus changes of patients every day.